The enzyme MAPK4 may be a novel therapeutic target for triple-negative breast cancer!

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The enzyme MAPK4 may be a novel therapeutic target for triple-negative breast cancer!

Nature Communications: The enzyme MAPK4 may be a novel therapeutic target for human triple-negative breast cancer!

More and more research evidence now shows that the enzyme MAPK4 may be involved in cancer growth and resistance to specific therapies.

Recently, an article published in the international journal Nature Communications entitled “MAPK4 promotes triple negative breast cancer growth” In the research report “and reduces tumor sensitivity to PI3K blockade”, scientists from Baylor College of Medicine and other institutions found that MAPK4 also seems to play an important role in the occurrence of triple-negative breast cancer, which is a very limited treatment option. devastating cancer.

By analyzing public genomic databases, the researchers found that a large number of triple-negative breast cancer patients express high levels of MAPK4, and that eliminating MAPK4 reduced the growth of human triple-negative breast cancer cells in animal models and made cancer cells resistant to blocking PI3K.

PI3K is a signaling pathway that promotes cancer growth, and the findings support further research by scientists to investigate whether targeting MAPK4 in triple-negative breast cancer could improve cancer therapy.

“In this study, we combined two long-term interests in our lab, namely investigating the critical role MAPK4 plays in human cancers and better understanding breast cancer, the most commonly diagnosed disease globally,” said researcher Feng Yang. In particular, this study focuses on triple-negative breast cancer, one of the most difficult-to-treat breast cancer subtypes;

first, the researchers analyzed 817 human breast cancers from the Cancer Genome Atlas database Gene expression profiles in samples, including multiple breast cancer subtypes, found that MAPK4 expression was elevated in 30% and more of basal-like breast cancer subtypes (70%-80% of which were triple negative breast cancers).

In addition, the researchers analyzed MAPK4 expression in a collection of breast cancer patient-derived xenografts (PDX) collected from Baylor Cancer Research Center, most of which were triple-negative breast cancers, PDX refers to an animal model of human cancer , which closely reproduces the cancer profile in the human body, and in a large subset of PDX tumors in triple-negative breast cancer, the researchers also found elevated MAPK4 expression.

Previous studies have shown that MAPK4 plays a role in promoting carcinogenesis in other cancer types, such as prostate cancer, and finding that MAPK4 levels are elevated in an important subtype of triple-negative breast cancer may prompt researchers to investigate whether MAPK4 can also promote the occurrence of triple-negative breast cancer.

In seven different human triple-negative breast cancer cell lines, some of which expressed MAPK4 high and some of which were low, the researchers then manipulated the gene expression levels of MAPK4, when MAPK4 was knocked down or eliminated by knockout methods. , the researchers found that the growth of cancer cells was significantly slowed down, which indicates that MAPK4 plays an important role in the development of triple-negative breast cancer.

The researchers also increased MAPK4 levels in low-expressing triple-negative breast cancers, which in turn promoted cancer cell growth, findings that support a critical role for MAPK4 in triple-negative breast cancer growth.

The enzyme MAPK4 may be a novel therapeutic target for triple-negative breast cancer! Image source: https://www.nature.com/articles/s41467-021-27921-1

Subsequently, Yang and his colleagues studied the molecular mechanism behind MAPK4 in triple-negative breast cancer to promote cancer. Previously, researchers found that MAPK4 may promote other cancers by activating a cancer-promoting signaling pathway called AKT in cells.

The growth of cancer types, the researchers found in this paper, may also be the case in triple-negative breast cancer.

Triple-negative breast cancer can activate AKT through two independent mechanisms, one mediated by MAPK4 and the other mediated by an enzyme called PI3K. “We all know that alterations in the PI3K pathway are very common in triple-negative breast cancer, but the therapeutic benefit of PI3K inhibitors is very limited,” said researcher Yang. “In this paper, we propose a new mechanism that may help explain inhibition.” Why would the drug lack the corresponding efficacy.

The researchers pointed out that inhibiting PI3K may allow cells to activate AKT through MAPK4, allowing cells to continue to grow; to confirm this idea, the researchers found that knocking out MAPK4 may cause cells to become sensitive to PI3K inhibitors and can Reduced cancer growth; in addition, overexpression of MAPK4 in low-expressing triple-negative breast cancer may allow cells to resist the effects of PI3K inhibitors and continue to promote their growth.

The researchers said that the study in this paper may provide a new therapeutic opportunity for triple-negative breast cancer based on MAPK4 expression, which may include a new combination of inhibitors to help control cancer growth, although this may require further development. research to support this view.

Taken together, our findings suggest that high MAPK4 expression may define a large subset or subtype of triple-negative breast cancer responsive to MAPK4 blockade, whereas targeting within a subset/subtype of triple-negative breast cancer Acting on MAPK4 may not only inhibit cancer growth, but also make tumors more sensitive to PI3K blockade.

Refereence:

MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade. Nat Commun 13, 245 (2022). doi: 10.1038/s41467-021-27921 -1

The enzyme MAPK4 may be a novel therapeutic target for triple-negative breast cancer!

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